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Antibodies and their uses for diagnosis and treatment of cytomegalovirus infection and associated diseases

a technology of cytomegalovirus and antibodies, applied in the field of methods of diagnosing and treating cytomegalovirus diseases, can solve the problems of high risk of developing life-threatening cmv disease, mental retardation and developmental disability, and immunocompromised organ transplant recipients or individuals infected with human immunodeficiency virus (hiv)

Inactive Publication Date: 2013-04-25
TECHNION RES & DEV FOUND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides an antibody that specifically binds to a MHC molecule that is complexed with a cytomegalovirus (CMV) pp65 or pp64 peptide. This antibody does not bind to the MHC molecule or the peptide in the absence of each other. The antibody can be used for detecting CMV-infected cells, diagnosing CMV infection, and treating CMV-related diseases. The invention also provides a multivalent form of the antibody and a pharmaceutical composition containing it. The technical effects of the invention include improved detection and diagnosis of CMV infection and improved treatment of CMV-related diseases.

Problems solved by technology

Primary infection with the virus results in a life long persistence in a latent form and is therefore generally asymptomatic in healthy adults.
However, some individuals, such as immuno-compromised organ transplant recipients, or individuals infected with human immunodeficiency virus (HIV), are at high risk of developing life threatening CMV disease due to CMV reactivation.
In addition, CMV has emerged in recent years as the most important cause of congenital infection in the developed world, commonly leading to mental retardation and developmental disability.
However, the use of these drugs may be associated with serious side effects such as kidney damage, neutropenia and hypocalcemia.

Method used

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  • Antibodies and their uses for diagnosis and treatment of cytomegalovirus infection and associated diseases
  • Antibodies and their uses for diagnosis and treatment of cytomegalovirus infection and associated diseases
  • Antibodies and their uses for diagnosis and treatment of cytomegalovirus infection and associated diseases

Examples

Experimental program
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Effect test

example 1

Selection and Cloning of Recombinant Antibodies Specific for HLA-A2-PP65 Complex

[0226]Experimental Results

[0227]Selection of Recombinant Antibodies Specific for HLA-A2 / pp65 Complexes

[0228]Recombinant peptide-HLA-A2 complexes that present the pp65495-503 (SEQ ID NO:3) CMV-derived peptide were generated using a single-chain MHC (scMHC) construct according to the method previously described previously (Denkberg G., et al., 2000). In this construct, the extracellular domains of HLA-A2 are connected into a single-chain molecule with β2m using a 15-aa flexible linker (the β2m is translationally fused upstream of the MHC heavy chain). The scMHC-peptide complexes were produced by in vitro refolding of inclusion bodies in the presence of the pp65 495-503 peptide (SEQ ID NO:3). The refolded scHLA-A2 / pp65 complexes were found to be pure, homogenous, and monomeric by SDS-PAGE and size exclusion chromatography analyses (data not shown). Recombinant scMHC-peptide complexes generated by this strat...

example 2

Characterization of HLA-A21pp65-Specific TCR-Like Recombinant Antibodies

[0235]Experimental Results

[0236]HLA-A2 / pp65-Specific TCR-Like Recombinant Antibodies Exhibit Binding Characteristics and Fine Specificity of a TCR-Like Molecule

[0237]The specificity of the two recombinant monoclonal Fab antibodies to the MHC-CMV peptide complex was tested by ELISA (FIGS. 1c and d). To determine the correct folding of the bound complexes and their stability during the binding assays, the ability of the complexes to react with the conformation-specific mAb, w6 / 32, that recognizes HLA complexes only when folded correctly and when containing peptide was monitored. As shown in FIGS. 1c and d, the soluble Fab Abs reacted only with the specific HLA-A2 / pp65 complex but not with other control HLA-A2 / peptide complexes containing viral epitopes derived from the TAX protein (e.g., TAX 11-19; SEQ ID NO:14), Gag (e.g., Gag 77-85; SEQ ID NO:9) or Pol (e.g., Pol 476-484; SEQ ID NO:10), or a variety of tumor-ass...

example 3

Generation of Multivalent Antibody Forms and their Binding to Peptide-Pulsed APCS

[0242]Experimental Results

[0243]Increased Avidity of Fab Tetramers to Peptide Pulsed APCs

[0244]Fab fragments w / o peptide isolated from the phage library are monovalent. To increase the avidity of these fragments, Fab tetramers were generated. This approach was previously used to increase the binding avidity of peptide-MHC complexes to the TCR or to increase the sensitivity of recombinant Ab molecules (Cloutier S M., et al., 2000). To form a Fab tetramer with H9, a BirA tag sequence for site-specific biotinylation was introduced at the C-terminus of the light chain. The Fab domains were expressed separately in E. coli and were refolded in vitro followed by purification and in vitro biotinylation using the E. coli-derived BirA enzyme (Cohen C J., et al., 2002). H9 Fab tetramers were generated with a fluorescently labeled streptavidin and their reactivity was examined by flow cytometry with JY pulsed cells...

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Abstract

Anti CMV antibodies are provided. Thus an antibody of the present invention comprises an antigen recognition domain capable of binding an MHC molecule being complexed with a cytomegalovirus (CMV) pp65 or pp64 peptide, wherein the antibody does not bind said MHC molecule in an absence of said complexed peptide, and wherein the antibody does not bind said peptide in an absence of said MHC molecule. Also provided are methods of using the antibodies.

Description

RELATED APPLICATIONS[0001]This application is a division of U.S. patent application Ser. No. 12 / 450,476 filed on Jan. 6, 2010, which is a National Phase of PCT Patent Application No. PCT / IL2008 / 000437 having International filing date of Mar. 27, 2008, which claims the benefit of priority of U.S. Provisional Patent Application Nos. 60 / 929,207 filed on Jun. 18, 2007 and 60 / 907,343 filed on Mar. 29, 2007. The contents of the above applications are all incorporated herein by reference.FIELD AND BACKGROUND OF THE INVENTION[0002]The present invention, in some embodiments thereof, relates to methods of diagnosing and treating cytomegalovirus diseases and, more particularly, but not exclusively, to antibodies capable of same.[0003]Of all the human herpesviruses described to date, infection with cytomegalovirus (CMV) is considered to be the main cause of morbidity and mortality. Approximately 70% of the world population are carriers of the virus. Primary infection with the virus results in a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/08
CPCA61K2039/505C07K16/088C07K16/2833C07K2317/92C07K2317/32C07K2317/55C07K2317/21A61P35/00C07K16/089
Inventor MAKLER, ORYANREITER, YORAM
Owner TECHNION RES & DEV FOUND LTD
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